In a recent study published on bioRxiv* preprint server, researchers compared the efficacy of bioengineered soluble angiotensin-converting enzyme-2 (ACE-2) in protecting the brain during coronavirus disease 2019 (COVID-19).
Studies have noted the potential of ACE2 proteins in neutralizing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using human organoids. The cell model designed in this study expressed human ACE2, an important receptor for SARS-CoV-2 entry into human cells, and transmembrane serine protease 2 (TMPRSS2), a protease important for the internalization of the SARS-CoV-2-ACE2 complex. .
The k18-hACE2 model was shown to be lethal when infected with wild-type (WT) SARS-CoV-2 and mimics the severe lung disease seen in humans. Although there is ample evidence for the significant brain injury reported by the model, the reason for the universal lethality is still unknown.
In this study, the researchers investigated the impact of ACE2 618-DDC-ABD, a bioengineered soluble ACE2 protein with sufficient duration of action and strong binding affinity to SARS-CoV-2.
In the k18-human ACE2 (hACE2) mouse, the team compared the impact of intraperitoneal (IP) versus intranasal (IN) administration of a soluble ACE2 protein called ACE2 618-DDC-ABD. According to the study protocol, animals that showed a weight loss of more than 20% of their body weight or showed a clinical score of three or more were sacrificed.
Four of nine healthy mice from the IN-pre group were sacrificed on day 5 to collect organs for comparison with the IP-pre group, while the other five mice belonging to the IN-pre group lived until day 14, which was the last day. study day. In contrast, surviving mice in the IP-pre-group had to be killed by day seven due to worsening clinical assessment and weight loss.
The team used k18-hACE2 mice, which express human ACE2 in its entirety and are susceptible to SARS-CoV-2 infection. Five to nine days after infection, animals with this viral load always succumb to the disease. The researchers examined the effects before and after treatment with the ACE2 protein 618-DDC-ABD and compared the effects of intranasal (IN) and intraperitoneal (IP) administration using different methodologies. In pretreatment cohorts, ACE2 618-DDC-ABD was administered IV or IP to k18-hACE2 mice one hour before SARS-CoV-2 infection and then 24 and 48 hours for three doses. Control animals were administered bovine serum albumin (BSA) in phosphate-buffered saline (PBS) both IP and IN at doses and intervals similar to mice treated with ACE2 618-DDC-ABD.
All infected untreated control mice had to be sacrificed on the fifth day, had a severe loss of body weight and obtained a high clinical score. In mice given ACE2 618-DDC-ABD before and after viral inoculation, survival rates at day 5 were 90% in the IN-pre group and 40% in the IP-pre group. The survival rate was 0% in untreated infected controls at day 5. In addition, the IN-pre group had minimal weight loss and better clinical scores. In contrast, the IP-pre-group reported weight loss and poor clinical evaluation.
In mice given ACE2 618-DDC-ABD after viral inoculation, the survival rate was 30% at day 5 and 20% at day 14 in the IN+IP-post group. Furthermore, in the IN-post cohort, survival rates were 20% at day 5 and 10% at day 14. The IP-post group had a 20% survival rate at day 5 but a 0% survival rate at day 14.
On the fifth day, 0% of untreated and infected mice survived. The majority of mice administered ACE2 618-DDC-ABD after viral inoculation experienced significant weight loss and deterioration in clinical scores, while a few recovered and survived up to day 14.
There were no detectable brain antibodies in the IN-pre group. On the other hand, brain titers were increased in five of eight mice in the IP-pre cohort, which was significantly greater than in the IN-pre group. Brain virus titers in mice after treatment were slightly and not significantly lower than in infected untreated animals. However, brain titers were undetectable at day fourteen in the few survivors of the post-treatment groups. Lung SARS-CoV-2 titers of animals treated with ACE2 618-DDC-ABC.
Overall, the study findings showed that ACE2 618-DDC-ABD provides significantly better survival and organ protection when administered IN than IP or after viral inoculation and that reduction in brain titers is a major predictor of survival and organ protection.
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and therefore should not be considered conclusive, guiding clinical practice/health-related behavior, nor should they be treated as verified information.
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